A deficiency in brain acetylcholine (ACh) function has been implicated in a variety of neurologic and psychiatric disorders. If one were to develop an animal model in which one could simulate the neurochemical conditions which appear to cause these diseases in humans, it would then be feasible to explore mechanisms with which to reverse the situation and to alleviate, or possibly even cure, the specific disease states. This would require the availability of chemical agents which would selectively be taken up in cholinergic nerve terminals within the CNS, and would subsequently permanently disturb the normal equilibrium of synthetic processes in these nerve terminals. We therefore propose to synthesize and investigate three different classes of chemical analogs of choline (Ch), based upon their predicted potential as neurotoxins with particular affinity for the cholinergic nerve terminal. Once the compounds are synthesized by us and tested for chemical purity they will each be screened for gross pharmacological activity and toxicity. A subsequent screen for cholinergic activity will follow. This will include an analysis, both in the periphery and in the CNS, of the effect of the compounds on levels of Ch and ACh, high affinity transport of Ch, cholinergic enzyme activity, cholinergic receptor binding, and turnover rate of ACh in vivo. Histological verification of specific cholinergic neurotoxicity of the compounds will next be established following their intracerebral injection into specific cholinergic nuclei. The effect of these compounds on dopaminergic, GABA-ergic, and noradrenergic systems in specific regions of the CNS will subsequently also be investigated after similar treatment, in order to ascertain the extent of selective cholinergic activity which is inherent in the effect of the agents under investigation. The latter studies will include analyses of levels, high affinity uptake, synthetic enzyme activity, and specific receptor binding of the various neurotransmitter systems. The effect of the potential neurotoxins on cholinergic, dopaminergic and GABA-ergic systems in the chick iris will also be studied, after systemic administration. These studies will hopefully lead to the development of agents capable of providing a good animal model for the study and elucidation of factors inherent in a variety of debilitating diseases of psychiatric and neurologic importance.